The long term objective of this project is to understand the relationship between the regulation of gene expression and nuclear substructure. Recent reports indicate that, soon after they are transcriptionally induced, genes in the model eukaryote Saccharomyces cerevisiae move to the nuclear periphery and associate with nuclear pore complexes. Specific Aim 1 is to use a single cell assay for regulated gene expression to determine the relationship between perinuclear gene anchoring and the ON and OFF transcriptional states. Specific Aim 2 is to explore the possibility that movement to the nuclear periphery is a universal property of transcriptionally induced genes. If not it will be important to determine whether transcriptionally active genes not anchored at the nuclear periphery become anchored elsewhere in the nucleus, for example within the nucleolus. Understanding these and other related aspects of gene regulation is key to the development of effective therapeutics for human diseases, since improperly regulated transcription is often responsible for congenital disorders and cancer. For example, the neurodegenerative disease spinocerebellar ataxia 7 results from a trinucleotide expansion in the SCA7 subunit of the chromatin modifying TFTC complex. These studies will take advantage of the integrated approach, including genetic, cell biological, and biochemical analyses, that is possible in the S. cerevisiae model system. The ease with which this organism can be grown and manipulated also makes it an ideal choice in providing research opportunities for undergraduate students.